miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells
miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells
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DOI：
10.1074/jbc.m110.160069
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发表时间：
2010-11-12
影响因子：
4.8
通讯作者：
Xu, Lan
中科院分区：
文献类型：
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作者：
Cottonham, Charisa L.;Kaneko, Satoshi;Xu, Lan
TGF-β促进细胞迁移和侵袭，这是与这种细胞因子在晚期癌症中的促转移功能相关的属性。LIM 1863结肠癌类器官响应于TGF-β而经历上皮-间充质转化（EMT）。TNF-α显著加速了这一过程，我们发现在TGF-β/TNF-α的协同作用下，miR-21和miR-31的水平显著升高。与此一致，miR-21或miR-31的过表达显著增强了单独TGF-β对LIM 1863形态学变化的影响。更重要的是，transwell试验证明了miR-21和miR-31在LIM 1863运动性和侵袭性的TGF-β调节中的积极作用。miR-21和miR-31水平的升高也增强了其他结肠癌细胞系的运动性和侵袭性。我们提出了令人信服的证据表明，TIAM 1，一个胍交换因子的Rac GTdR，是一个直接的目标，miR-21和miR-31。事实上，在LIM 1863细胞中，miR-21/miR-31需要抑制TIAM 1以增强细胞迁移和侵袭。因此，我们发现miR-21和miR-31是TGF-β促进结肠癌细胞侵袭和转移的下游效应子。
TGF-beta promotes cell migration and invasion, an attribute that is linked to the pro-metastasis function of this cytokine in late stage cancers. The LIM 1863 colon carcinoma organoid undergoes epithelial-mesenchymal transition (EMT) in response to TGF-beta. This process is markedly accelerated by TNF-alpha, and we found that the levels of miR-21 and miR-31 were prominently elevated under the synergistic actions of TGF-beta/TNF-alpha. Consistent with this, overexpression of either miR-21 or miR-31 significantly enhanced the effect of TGF-beta alone on LIM 1863 morphological changes. More importantly, transwell assays demonstrated the positive effects of both miR-21 and miR-31 in TGF-beta regulation of LIM 1863 motility and invasiveness. Elevated levels of miR-21 and miR-31 also enhanced motility and invasiveness of other colon carcinoma cell lines. We present compelling evidence that TIAM1, a guanidine exchange factor of the Rac GTPase, is a direct target of both miR-21 and miR-31. Indeed in LIM 1863 cells, suppression of TIAM1 is required for miR-21/miR-31 to enhance cell migration and invasion. Therefore, we have uncovered miR-21 and miR-31 as downstream effectors of TGF-beta in facilitating invasion and metastasis of colon carcinoma cells.